title: Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer.
abstract: Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure, and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal-epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6(f/f)) mice were crossed to Wnt7a-Cre mice (Wnt7a(cre+)Mig-6(f/f)). Wnt7a(cre+)Mig-6(f/f) mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in subepithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7a(cre+)Mig-6(f/f) mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7a(cre+)Mig-6(f/f) mice was prevented by progesterone treatment, whereas this treatment had no effect in PR(cre/+)Mig-6(f/f) mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERα signaling. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.forename: Dong-Kee
authors.initials: DK
authors.lastname: Lee
authors.forename: Sung-Nam
authors.initials: SN
authors.lastname: Cho
authors.forename: Grant D
authors.initials: GD
authors.lastname: Orvis
authors.forename: Richard R
authors.initials: RR
authors.lastname: Behringer
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.forename: Bon Jeong
authors.initials: BJ
authors.lastname: Ku
authors.forename: Adrienne S
authors.initials: AS
authors.lastname: McCampbell
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D048708:Cell Growth Processes / Q000502:physiology; D004714:Endometrial Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D005260:Female; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D011374:Progesterone / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D014599:Uterus / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C475819:Errfi1 protein, mouse; D047628:Estrogen Receptor alpha; D004967:Estrogens; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011980:Receptors, Progesterone; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse; D011374:Progesterone; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases